Asymmetric Catalysis upon Helically Chiral Loratadine Analogues Unveils Enantiomer-Dependent Antihistamine Activity

Analogues of the conformationally
dynamic Claritin (loratadine)
and Clarinex (desloratadine) scaffolds have been enantio- and chemoselectively N-oxidized using an aspartic acid containing peptide catalyst
to afford stable, helically chiral products in up to >99:1 er.
The
conformational dynamics and enantiomeric stability of the N-oxide products have been investigated experimentally and
computationally with the aid of crystallographic data. Furthermore,
biological assays show that rigidifying the core structure of loratadine
and related analogues through N-oxidation affects
antihistamine activity in an enantiomer-dependent fashion. Computational
docking studies illustrate the observed activity differences.